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Glycogen synthase kinase 3β (GSK3β) was originally identified as a regulator for glycogen metabolism and is now an important therapeutic target for a variety of brain disorders including neurodegenerative diseases due to it's pivotal role in cellular metabolism, proliferation and differentiation. In the development of stroke therapies focusing on tissue repair and functional recovery, promoting neurogenesis is a main approach in regenerative medicine. In the present investigation, we explored the effects of a GSK3β specific inhibitor, 6-Bromoindirubin-3′-oxime (BIO), on regenerative activities of neuroblasts in the subventricular zone (SVZ) and functional recovery after focal cerebral ischemia. Adult C57/BL mice were subjected to occlusion of distal branches of middle cerebral artery (MCA) supplying the sensorimotor barrel cortex. Three days later, BIO (8.5 μg/kg, i.p.) was administered every 2 days until sacrificed at 14 or 21 days after stroke. The BIO treatment significantly increased generation of neuroblasts labeled with BrdU and BrdU/doublecortin (DCX) in the SVZ. Comparing to vehicle controls, increased number of neuroblasts migrated to the peri-infarct region where they differentiate into mature neurons. Along with the elevated BDNF expression at the peri-infarct area, the number of newly formed neurons was significantly increased. BIO treatment significantly enhanced sensorimotor functional recovery after the focal ischemia. It is suggested that the GSK3 signaling may be a potential therapeutic target for regenerative treatment after ischemic stroke.

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The neuropeptide oxytocin (OT) plays a critical role in modulating social behavior across a wide range of vertebrate species. In humans, intranasal oxytocin (INOT) has been shown to modulate various aspects of social behavior, such as empathy, trust, in-group preference, and memory of socially relevant cues. Most INOT studies employ cross-sectional designs despite the enhanced statistical power and reduction in error variance associated with individual differences characteristic of within-subject designs. Using the Prisoner Dilemma task, which models a real-life dyadic social interaction, our group has systematically explored the effect of INOT on social cooperation and non-cooperation using a cross-sectional design. In the current study, we investigated if the main findings from our cross-sectional study could be replicated in a within-subject design using the same paradigm and whether new findings would emerge. We found OT to attenuate the ventral tegmental area response to reciprocated cooperation in women, an effect that is also present in our cross-sectional sample. However, other cross-sectional findings, especially those found in men, were not observed in this within-subject study. We hypothesize that the discrepancy can be explained by differing OT effects based on the degree of stimulus novelty/familiarity. Our within-subject study also revealed new effects not found previously in our cross-sectional study. Most importantly, OT treatment on scan 2 blocked amygdala habituation to unreciprocated cooperation found in a group that received placebo on both scans among men. Our results suggest that exogenous OT reduces the salience of positive social interactions among women and prevents habituation to negative social interactions among men. These findings may have implications for the potential clinical utility of OT as a treatment for psychiatric disorders.

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Cigarette smokers with schizophrenia exhibit more severe cognitive dysfunction during smoking abstinence than control smokers, and cognitive deficits are associated with higher rates of smoking cessation failure (Dolan et al., 2004; Wing et al., 2012). The pro-cognitive effects of nicotine may result from enhanced dopamine (DA) release in the prefrontal cortex (PFC). Catechol-O-methyltransferase (COMT) is the primary enzyme responsible for DA metabolism in cortical brain regions. Allelic variation at a single nucleotide polymorphism (SNP) in the COMT gene at position 158 in the membrane-bound form (rs4680 or Val158met) strongly influences the level of COMT activity.

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Lesch-Nyhan disease (LND) is a rare, X-linked recessive neurodevelopmental disorder caused by deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGprt), an enzyme in the purine salvage pathway. HGprt has two functions; it recycles hypoxanthine and guanine. Which of these two functions is more relevant for pathogenesis is unclear because some evidence points to hypoxanthine recycling, but other evidence points to guanine recycling. In this study, we selectively assayed hypoxanthine (Hprt) and guanine (Gprt) recycling in skin fibroblasts from 17 persons with LND, 11 with an attenuated variant of the disease (LNV), and 19 age-, sex-, and race-matched healthy controls (HC). Activity levels of both enzymes differed across groups (p < 0.0001), but only Gprt distinguished patients with LND from those with LNV (p < 0.05). Gprt also showed slightly stronger correlations than Hprt with 13 of 14 measures of the clinical phenotype, including the severity of dystonia, cognitive impairment, and behavioral abnormalities. These findings suggest that loss of guanine recycling might be more closely linked to the LND/LNV phenotype than loss of hypoxanthine recycling.

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Prenatal exposure to chlorpyrifos (CPF), an organophosphorus insecticide, has long been associated with delayed neurocognitive development and most recently with decrements in working memory at age 7. In the current paper, we expanded the previous work on CPF to investigate how additional biological and social environmental factors might create or explain differential neurodevelopmental susceptibility, focusing on main and moderating effects of the quality of the home environment (HOME) and child sex. We evaluate how the quality of the home environment (specifically, parental nurturance and environmental stimulation) and child sex interact with the adverse effects of prenatal CPF exposure on working memory at child age 7. years. We did not observe a remediating effect of a high quality home environment (either parental nurturance or environmental stimulation) on the adverse effects of prenatal CPF exposure on working memory. However, we detected a borderline significant interaction between prenatal exposure to CPF and child sex (B (95% CI) for interaction term = -1.714 (-3.753 to 0.326)) suggesting males experience a greater decrement in working memory than females following prenatal CPF exposure. In addition, we detected a borderline interaction between parental nurturance and child sex (B (95% CI) for interaction term =1.490 (-0.518 to 3.499)) suggesting that, in terms of working memory, males benefit more from a nurturing environment than females. To our knowledge, this is the first investigation into factors that may inform an intervention strategy to reduce or reverse the cognitive deficits resulting from prenatal CPF exposure.

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Improvements in task performance due to repeated testing have previously been documented in healthy and patient populations. The existence of a similar change in performance due to repeated testing has not been previously investigated at the level of gait kinematics in the post-stroke population. The presence of such changes may define the number of testing sessions necessary for measuring a stable baseline of pre-training gait performance, which is a necessary prerequisite for determining the effectiveness of gait interventions. Considering the emergence of treadmills as a popular tool for gait evaluation and retraining and the common addition of functional electrical stimulation (FES) to gait retraining protocols, the stability of gait kinematics during the repeated testing of post-stroke individuals on a treadmill, either with or without FES, needs to be determined. Nine individuals (age: 58.1. ± 7.3 years), with hemi-paresis secondary to a stroke (onset: 7.3. ± 6.0 years) participated in this study. An 8-camera motion analysis system was used to measure sagittal plane knee and ankle joint kinematics. Gait kinematics were compared across two (N= 9) and five (N= 5) testing sessions. No consistent changes in knee or ankle kinematics were observed during repeated testing. These findings indicate that clinicians and researchers may not need to spend valuable time and resources performing multiple testing and acclimatization sessions when assessing baseline gait kinematics in the post-stroke population for use in determining the effectiveness of gait interventions.

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Background: There is mounting evidence for a connection between the gut and Parkinson's disease (PD). Dysbiosis of gut microbiota could explain several features of PD. Objective: The objective of this study was to determine if PD involves dysbiosis of gut microbiome, disentangle effects of confounders, and identify candidate taxa and functional pathways to guide research. Methods: A total of 197 PD cases and 130 controls were studied. Microbial composition was determined by 16S rRNA gene sequencing of DNA extracted from stool. Metadata were collected on 39 potential confounders including medications, diet, gastrointestinal symptoms, and demographics. Statistical analyses were conducted while controlling for potential confounders and correcting for multiple testing. We tested differences in the overall microbial composition, taxa abundance, and functional pathways. Results: Independent microbial signatures were detected for PD (P = 4E-5), participants' region of residence within the United States (P = 3E-3), age (P = 0.03), sex (P = 1E-3), and dietary fruits/vegetables (P = 0.01). Among patients, independent signals were detected for catechol-O-methyltransferase-inhibitors (P = 4E-4), anticholinergics (P = 5E-3), and possibly carbidopa/levodopa (P = 0.05). We found significantly altered abundances of the Bifidobacteriaceae, Christensenellaceae, [Tissierella ceae], Lachnospiraceae, Lactobacillaceae, Pasteurellaceae, and Verrucomicrobiaceae families. Functional predictions revealed changes in numerous pathways, including the metabolism of plant-derived compounds and xenobiotics degradation. Conclusion: PD is accompanied by dysbiosis of gut microbiome. Results coalesce divergent findings of prior studies, reveal altered abundance of several taxa, nominate functional pathways, and demonstrate independent effects of PD medications on the microbiome. The findings provide new leads and testable hypotheses on the pathophysiology and treatment of PD.